Jump to

Abstract

Metabolic derangements in the body are tightly linked with cardiovascular disease. We have earlier established the association between genetic variants of USF1 with familial combined hyperlipidemia and its component traits, TG and cholesterol in Finnish families. In the current study we have conducted a detailed analysis of the effects of USF1 on metabolic parameters using both in vivo and in vitro models.

We generated a congenic strain of Usf1 knockout (-/-) (11 males, 29 females) mice which along with their +/− and +/+ (27 M, 31 F) littermates were fed with Western diet rich in TG and cholesterol for 5 months. The Usf1 -/- mice displayed both elevated cholesterol (p<0.001) and phospholipids in their plasma. In human hepatoma cells (HuH7), using USF1 targeting siRNAs, we showed that APOA1 transcription and secretion were elevated in USF1 silenced cells in line with the animal model. USF1 overexpression also inhibited the activity of a 2000 bp APOA1 promoter-linked luciferase (p<0.05), raising the possibility of APOA1 being be a direct target gene of USF1. The Usf1 -/- mice had lower plasma total and VLDL TG as compared to their +/+ littermates, which is due to increased lipolysis. This was evidenced by -/- mice having higher activity and expression (p<0.01) of lipoprotein lipase in the liver, muscle, and adipose tissue.

We observed that despite having increased food consumption and being physically less active than +/+ mice, the Usf1 -/- mice were actually protected from obesity during Western diet and also showed an increased sensitivity to insulin during insulin tolerance test. Expression analysis from their adipose tissue revealed an increased expression of complexes of the mitochondrial respiratory chain (p<0.001) which was evidenced by both increased VO2 and VCO2, suggesting a higher overall metabolic rate for the -/- mice. These changes were not observed at an early age, but after 5 months of Western diet.

Our study establishes the critical role of USF1 at the crossroads between metabolic and cardiovascular homeostasis. Since the loss-of-function of USF1 caused a favorable blood lipid phenotype and protection from obesity during Western diet, we hypothesize that its knockdown effect in appropriate tissues has favorable cardiovascular and metabolic effects.